Immunomodulating effects of second-generation calcium channel blockers on experimental heart transplantation

The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypot hesized that exposure to clinically relevant concentrations may have a sign ificant immunomodulatory potential. The effects of various second-generatio n CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allog raft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation o f the donor heart, allograft recipients were exposed to felodipine (31 mu g /kg/day), amlodipine (25 mu g/kg/day), mibefradil (3 mg/kg/day) or clentiaz em (2.5 mg/kg/day). Other a I log raft recipients were treated with low-dos e cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 mu g/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 m g/kg/day). All drugs were given daily by gavage. Median survival time of un treated cardiac allografts was 6.5 days. When given alone, not all the seco nd-generation CCBs elicited a positive effect: the dihydropyridines felodip ine and amlodipine were ineffective (median survival time was 6.5 and 7.0 d ays, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzoth iazepine clentiazem produced the most significant result (median survival t ime = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 da ys), while clentiazem had a significant positive effect. These data indicat e that second-generation CCBs differ in their immunomodulatory potential. T hese observations of pharmacodynamic specificity appear to be related to di fferences in their chemical structure as well as their interaction with oth er sites than the calcium channel.